Pain Pump Law Blog : Medical Device and Malpractice Lawyer & Attorney for Local Anesthetic Infusion Pump & Post-Operative Infection Cases

I am working on another post relating to FDA regulation of pain pumps, but expect it may be a week or two before I am able to complete it.  In the meantime, I thought I would share an article I recently came across----Disposable Infusion Pumps by Skryabina and Dunn.  It contains useful explanations of how some of the most common types of these pumps actually function.

These devices are used for many purposes beyond that of a "pain pump"--delivering local anesthetics post-operatively at or near a surgical site.  These include the delivery of other medications, including chemotherapy, antimicrobials, antibiotics, as well as the delivery of anesthetics or analgesics by other routes, eg., continuous epidural, peripheral nerve block, and i.v..  The authors provide concise descriptions of the mechanisms of several types of non-electric pumps including elastomeric, positive-pressure (spring-powered and gas-pressured powered), negative-pressure (vacuum), and patient-controlled analgesia (PCA) pumps. 

The flow rates of medications through disposable pumps are significantly inaccurate--typically within +/-15% or even +/-20%.  (Compared to +/-3% with electronic syringe pumps and +/-5% with electronic volumetric pumps).  I believe most pain pump manufacturers include the +/-15% figures in their written materials--see, eg. the flow rate table included in the product Insert for the On-Q Pump with Fixed Flow Rate. 

Nonetheless, I assume most surgeons who use a pain pump labeled with a 2 ml/hr flow rate are likely to believe that the device delivers only 48 ml of local anesthetic in the first 24 hours.  In fact, the same flow rate table in the Insert for the On-Q Pump (along with all other documents for the On-Q I've seen) shows that a 100 ml pump will actually deliver 65 ml in the first 24 hours.  For the first several hours, the flow rate is actually 2.5 ml or higher. 

If the anesthetic is 0.50% Marcaine, 65 ml means 325 mg.  The maximum 24 hour dose for Marcaine is 400 mg and, as I've stressed before, this is based on the risk of systemtic toxicity (neurological or cardiac) and not local (tissue) toxicity.  Surgeons commonly use additional injections of local anesthetics around surgical sites during procedures.  Thus, it would take only an additional 15 ml of 0.50% Marcaine, along with a 100 ml 2 ml/hr. pump, to reach a 400 mg dose in the first 24 hours after surgery. 

I believe many pain pump manufacturers have blithely assumed that any 24 hour dose of Marcaine as long as it remains less than 400 mg, in most any part of the body, regardless of the concentration, and regardless of the route of administration (continuous infusion vs. others), is inherently safe.  For all who have sustained injuries from pain pumps caused by local anesthetic toxicity, this has been a tragically flawed assumption. 

 

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In my last post, I discussed a 2008 research article which found a relationship (in both duration of exposure and concentration) between Bupivacaine and muscle damage.   In a prior post, I sought to summarize some earlier articles which also discuss local anesthetics and myotoxicity.  Given the significant evidence that seems to support this troubling relationship, I've wondered if there are any efforts to develop alternatives to existing local anesthetics, especially Bupivacaine.

In "Prolonged Duration Local Anesthesia With Minimal Toxicity," (2009) Hila Epstein-Barash and colleagues (which include Dr. Daniel S. Kohane, one of the authors of the above 2008 article) describe a compound which has powerful anesthetic properties but with causes little damage to human cells.  The authors explain the motivation behind their research:

The development of local anesthetics to provide prolonged analgesia from a single injection has encountered 3 principal challenges: inadequate duration of action, systemic toxicity, and adverse local tissue reaction. The purpose of this research was to produce a local anesthetic lasting many days without those detrimental sequelae.

Conventional local anesthetics are intrinsically myotoxic. They are also myotoxic when released from a wide range of delivery systems, even when the delivery systems themselves are minimally toxic. The myotoxicity of bupivacaine increases dramatically over extended durations of exposure, suggesting that myotoxicity may be an inevitable consequence of sustained release of such compounds. (citations omitted)

The article is quite technical and I don't begin to understand all of its complexities.  What I do grasp, however, is that the researchers developed a formulation called STX (saxitoxin) which is a site 1 sodium-channel blocker, which blocks nerves in a different manner than conventional local anesthetics.  Site 1 sodium channel blockers are known not to cause myo- or neuro-toxicity.  The authors were interested in providing a controlled release of STX over an extended period of time in order to attempt a prolonged nerve block, so they used liposomes--tiny bubbles made of the same material as cell membranes--as a delivery vehicle for the medication.  The authors reported that in cell cultures of rats, Bupivacaine but not STX was myo- and neuro-toxic in both time and concentration dependent manners.  The authors state these results suggest that controlled release of STX and similar compounds can provide very prolonged nerve blocks with minimal systemic and local toxicity.

I have no idea how far in the future STX might be approved and available for human use.  However, it is encouraging to know that there are scientists concerned enough about the shortcomings of Bupivacaine and other conventional local anesthetics who are working to create safer alternatives. 

 

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In a recent article entitled, Local Myotoxicity from Sustained Release of Bupivacaine from Microparticles, Padera, et.al., state:

Myotoxicity is a well-recognized side effect of local anesthetic administration, perhaps particularly of extended exposure, whether from controlled-release methodologies or from catheter-related methods. Occasionally, the consequences can be clinically significant.

These authors studied a variety of controlled-release systems designed to prolong the duration of local anesthetics. The authors gave rats sciatic nerve blocks by injecting them with different bupivacaine solutions and found muscle damage in all of the animals, with greater damage from the encapsulated (higher concentrated) bupivacaine particles than from free bupivacaine (the 0.5% bupivacaine hydrochloride solution commonly used in surgeries). Local anesthetic-induced myotoxicity generally recovers rapidly, often within two weeks, however, the authors noted some controlled-release formulations cause myotoxicity at least as far out as one month after injection.

One possible explanation of this observation is that local anesthetic myotoxicity is time-dependent. Myotoxicity was found to increase with the concentration of bupivacaine, but also markedly with duration of exposure. For example, 62 +/- 12% of cells exposed to 0.025% bupivacaine survived a 2-hour exposure, whereas only 1 +/- 2% survived at 3 weeks. It is important to note that this is an extremely weak concentration of bupivacaine: twenty times weaker than 0.5%. The authors go on to say:

This finding raises the possibility that myotoxicity could be an inevitable concomitant of long-term exposure to conventional (amino-amide and amino-ester) local anesthetics, irrespective of the technology used to deliver them. Myotoxicity is a well-known occurrence in clinical or investigational use of conventional local anesthetics. Although it can have severe consequences, it has not generated much clinical concern. In fact, intramuscular local anesthetic injection is a standard treatment for trigger points in myofascial pain syndromes, and local anesthetic myotoxicity is generally reversible. The distinction that must be made, however, is that those treatments generally involve a single-shot drug injection with a brief duration, whereas microparticulate systems can result in very high local concentrations and/or weeks of local anesthetic exposures.

The findings of this article raise alarming concerns about pain pumps. The continuous repeated exposure to tissues (especially around a healing surgical wound) with local anesthetics (known to cause cell damage and even death) over a period of 48 to 120 hours seems much more likely to result in cell damage than if the same volume of the medication was injected at a single time.

The potential for irreversible cell damage—necrosis—caused by local anesthetics and infusion pumps seems site-dependent. Pain pump manufacturers have acknowledged as much. I-Flow, in its current Directions For Use for the On-Q pump states:

To avoid complications in restrictive spaces use the lowest flow rate, volume and drug concentration required to produce the desired result. In particular:

Avoid placing the catheter in the distal end of extremities (such as nose, ears, fingers, groin area, penis, toes, etc.) where fluid may build up as this may lead to ischemic injury or necrosis.

However, this warning (also contained in I-Flow’s Technical Bulletin on hand and foot surgery) is too limited in scope. While it would apply to bunionectomies, it does not apply to any other foot or ankle surgeries, including catheter placements in the top of the foot near the ankle. This is certainly a restrictive space, made even more so when it is under a compression dressing following surgery. Two pain pump cases I have involve foot surgeries with catheter placements in this location, with disastrous complications to the patients.

The more often I read about the toxicity of local anesthetics, especially bupivacaine, the more I suspect it routinely causes damage to the patient (maybe always causes damage), but that harm is often not detected because the affected cells regenerate or scarring or other damage occurs which may not manifest itself until far in the future. Even when the damage arises to visible injury, many of these injuries are not properly diagnosed as local anesthetic tissue toxicity, but rather as post-operative infections. This is what occurred in the two foot surgery cases I mentioned above.

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I recently came across a post by Armand Rosetti which summarized some news articles relating to I-Flow Corporation and its Chief Executive, Donald Earhart. Especially interesting are some statements Mr. Earhart made in a November 5, 2008 conference call with investment analysts regarding the company’s third quarter earnings.  Earhart was answering questions regarding the status of the shoulder chondrolysis lawsuits, and said:

I’ve said this argument before on the conference calls, is that a pain pump or a delivery device, whether it be a syringe or one of our pumps delivering a drug, how do you blame the device, because there’s no way the device can cause the disappearance of cartilage. It would have to be whatever is delivered into the site or would have to be the technique by the doctor or would have to be the sutures or it would have to be the staples or it would have to be something else used during the surgery, but it can’t be our pump, because our pump can’t cause cartilage to disappear…. It’s like using a syringe to deliver a narcotic. We can’t be held responsible for the side effects, if I’m the syringe manufacturer, of the drug.

This raises an important point.  Clearly, it is the toxicity of the local anesthetic that causes the direct harm to the patient--whether the result be the destruction of shoulder or other joint cartilage, tissue necrosis around a surgical site, or other injury.  How then can a plaintiff reasonably seek to blame the maker of the device and not the drug?  Because a pain pump manufacturer retains a legal responsibility to patients to provide that their devices may be safely used with local anesthetics in a manner intended by the manufacturer of the local anesthetic.  Continuous infusion through a pain pump is not a listed intended use of a local anesthetic; it is an off-label use.   A statement such as I-Flow makes in its current Directions for Use for the On-Q pump, “medications or fluids must be administered per instructions provided by the drug manufacturer,” has little meaning when the use in question is not addressed by the manufacturer. 

Mr. Earhart and I-Flow appear to take for granted that continuous infusion is no different than the uses approved by the local anesthetics manufacturers. I contend pain pumps represent a categorically different use both because of the larger volume of local anesthetic infused and the significantly greater duration of exposure of the affected tissues to the medication. For example, a single bolus dose of 100 mg (20 ml) of Marcaine to produce a nerve block may well create less risk of local tissue toxicity than continuously infusing smaller volumes—2ml/hr—but with a larger total volume 240 mg (100 ml) over a much longer time—2-5 days.

On the other hand, the uses to which a syringe is put--—local infiltration around a surgery site and injections to produce various types of nerve blocks—are approved uses by the drug manufacturer.  Because there are a variety of known risks of patient injury with their devices, pain pump manufacturers have a duty  to timely and adequately convey warnings of such risks to the physicians who use them. 

 

 

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A number of articles have reported a relationship between local anesthetics and myotoxicity—damage to muscle; for example: Zink, et.al. (2004), Zink, et.al. (2003), Irwin et.al., (2002), Nonaka, et.al. (1983). Published before the widespread use of pain pumps, a 1994 article by Hogan, et.al., begins with the following accepted generalizations:

All local anesthetics that have been tested are myotoxic. Procaine produces the least and bupivacaine the most severe injury. Injection of local anesthetics intramuscularly or into adjacent subcutaneous tissue results in myonecrosis. The extent of muscle injury from local anesthetics is dose dependent and worsens with serial administration.

Local anesthetics are injected into muscle for treatment of myofascial pain, in wound margins during surgery, and for neural blockage during surgical anesthesia.

The authors describe a female patient who underwent capsular release of the left shoulder. Because continuous passive shoulder motion and physical therapy were planned immediately following the surgery, a nerve block during and after the procedure was planned. A catheter was placed in the left interscalene groove at the level of the cricoid cartilage. Bupivacaine (0.5%) with epinephrine was injected incrementally to a total volume of 45 ml (200mg), producing sensory and motor blockade of the shoulder, arm, and hand.

When the woman began experiencing shoulder pain approximately 16 hours post-operatively, she received additional bolus doses of the 0.5% bupivacaine with epinephrine through the catheter. The doctors used additional injections of the same solution through the catheter when the woman’s shoulder pain did not resolve. After 34 hours, the catheter was removed. The total dose was 228 ml (1140 mg). The woman developed persistent pain in the left side of her neck. Imaging was suggestive of a tissue injury.  Approximately 8 weeks post-op, a muscle biopsy  showed injury to the muscle fibers.

Large doses of bupivacaine were used on the patient because of the authors’ desire to provide pain relief suitable for the expected post-operative manipulations of her shoulder. Because the injections failed to produce the desired effect, they suspected the catheter tip became dislodged.

According to the authors, while myotoxicity of local anesthetics has been widely produced in experimental settings, reports in human patients are uncommon. The authors’ next observations are why this article is interesting regarding pain pumps:

Local anesthetic injection for neural blocks only occasionally requires intramuscular injections of large volumes…. These are not usually repeated, and the injection site is difficult to examine. Small volumes are used with injections for intercostal, supraspinatus or musculocutaneous nerve blocks and with trigger point injections and stellate ganglion blocks.

Because experimental studies show myonecrosis after single injections of even minimal doses of local anesthetic, it is likely that myopathy occurs after most injections but is not recognized because of rapid and complete recovery.

Local pain for which trigger point injections are performed may disguise myopathic changes, and discomfort and dysfunction after injections performed for surgical anesthesia can be readily attributed to surgery or concealed by surgical pain. Splinting prevents tenderness from being identified. The pain of inflammation develops only after 3 or 4 days, and the appearance of atrophy takes longer; thus, these events frequently may be missed or not correlated to the administration of anesthetic agents. (My emphases)

Caveats: this 1994 article pre-dates the widespread use of pain pumps.  The authors utilized Bupivacaine (0.5%) with epinephrine. Several years ago, pain pump manufacturers began recommending against using local anesthetics with epinephrine. Further, the large volume of Bupivacaine injected into the woman’s shoulder undoubtedly exceeded the manufacturer of Bupivacaine’s maximum recommended dose of 400 mg within a 24-hour period. In light of the numerous recent reports of chondrolysis, the fact that such a large volume of Bupivacaine with epinephrine was injected into the woman’s shoulder near cartilage is alarming (although the authors seem to believe that the catheter had become dislodged from its original location).

Nonetheless, the article raises a number of concerns regarding continuously infused local anesthetics and pain pumps.  As the authors’ comments make clear, at the time this article was written, local anesthetics were typically used in relatively small amounts around the surgical site and to produce nerve blocks.   Even small amounts, however, routinely cause cells to die, but they typically regenerate without incident. Post-operative pain and inflammation often mask symptoms that may actually be associated with damage to tissues.

In small amounts, given the beneficial pain relief afforded by local anesthetics, the temporary harm they cause would seem to be an acceptable side effect.  What happens, though, when these drugs are continuously infused, in or near an open wound, in total volumes larger than commonly used in the past?   There must be factors that cause the usually temporary harm to tissues to take the form of more visible and potentially permanent complications such as wound dehiscence, blistering, sloughing, and necrosis.  These would seem to include:

• Local anesthetic volume
• Local anesthetic concentration
• Rate of infusion
• Duration of infusion
• Surgery/catheter site
• Patient-specific factors-age, weight, risk-factors

The pain pump and local anesthetic manufacturers have failed to properly considered these factors and, instead, make blanket, one-size fits all recommendations to surgeons. 

A bigger question:  Why is the medical community still so routinely using higher concentrations of Bupivacaine when it is known to cause damage to a variety of human cells-- cartilage, muscle, nerve, renal, and undoubtedly others?

 

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On February 19, the FDA approved a revised label for Marcaine (Bupivacaine Hydrochloride), manufactured by Hospira.  The label contains the following warning regarding the risk of chondrolysis:

Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.

This language generally seems appropriate to me, however, I fail to understand why the FDA permitted the following sentence, "There is insufficient information to determine whether shorter infusion periods are not associated with these findings."  This seems to be an ill-advised attempt by Hospira to create ambiguity about the safety of intra-articular infusion.   The FDA Alert which prompted this warning goes out of its way to note that intra-articular injections of local anesthetics in orthopedic procedures have been given for years without reported incidents of chondrolysis.  The FDA then flatly states:  Neither local anesthetics nor infusion devices are approved for an indication of continuous intra-articular infusion.

The revised Marcaine label also has the following language: 

There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. MARCAINE is not approved for this use.

Since the drug is not approved for this use, without regard to the duration of the infusion, why permit the slightest hint of confusion to remain in the label? Especially in light of the research of Constance R. Chu, M.D. that exposures even as short as 30 minutes cause massive death in cartilage cells. 

 

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